Green space exposure and colorectal cancer: A systematic review

Green space has been linked to colorectal cancer, but the evidence is still limited and inconclusive. This review aimed to investigate the relationship between green space and CRC. The studies were searched using three primary journal databases: PubMed, Scopus, and Web of Science. The retrieved citations were screened, and data from articles about GS exposure and CRC were extracted. The Newcastle-Ottawa Quality Assessment Form for Cohort Studies was used to evaluate the studies' quality. Five of the 1792 articles identified were eligible for the final review, which included five cohort studies published between 2017 and 2022. Each one article from the United States, the United Kingdom, France, Belgium, and Germany and All studies are of high quality. Four studies reported CRC incidence and one study reported CRC mortality from GS exposure. There was no significant association between GS attributes (Normalized Difference Vegetation Index (NDVI), surrounding greenness, surrounding green area, proximity to GS (agricultural lands, urban GSs, and forests), and count of recreational facilities and parks) with CRC. Only one study discovered that a healthier ecosystem was linked to a lower CRC risk. Although the evidence is still limited, the findings may indicate the presence of other factors in the relationship between GS and CRC. Future research should continue to focus on the variation of GS and the factors that influence it. Specific attention to the development of GS has the potential to produce benefits while mitigating cancer risk.


Introduction
Colorectal cancer is the most common gastrointestinal malignancy diagnosed in the world, with an estimated number of new cases in 2020 for both sexes, about 1.9 million and 900,00 deaths [1]. Years of research have identified several environmental CRC risk factors, yet the precise causes of colorectal neoplasms remain unknown [2].
Rapid economic growth, increased exposure to environmental and lifestyle risks, associated with the increased incidence of CRC [3]. The development of CRC further increased with the combination of environmental and individual-level risk factors, such as lifestyle and habits related to diet, smoking and alcohol consumption [4]. Exposure to GS also affects public health, e.g. in terms of prevalence of chronic disease [5], mental health (depression symptoms) [6] and mortality [7].
Green spaces are often associated with nature and contain green vegetation [8]. They are also closely related to physical activity because they can encourage walking, running, and playing [9]. Convincing evidence suggests that physical activity (of all types and intensities) lowers the risk of colon cancer, but no conclusion has been reached for rectal cancer [4].
(a) Population: adult participants with no gender or area restriction (b) Exposure: Studies that assessed the quantity or quality of green spaces on all types of natural and man-made green environments such as parks, playgrounds, coastal parks with vegetation, etc. were included as long as they were defined as green spaces by the authors. (c) Outcomes: Studies that examined CRC risk or outcomes, including prevalence, incidence and mortality (d) Study design: All observational and intervention studies, including randomised, quasi-randomised and non-randomised studies.
We excluded articles that did not refer to CRC, GS environment and CRC outcome or studies with non-human subjects, study protocols, conference abstracts, dissertations, reviews, qualitative studies, editorials, case studies and opinion articles. In the selection of articles, all authors (N.M., A.N., M.A, R.H.) were involved in reviewing the titles and abstracts of potentially eligible articles. Each article was independently reviewed by at least two authors. Any disagreements were resolved by discussion and consensus between two authors or with the help of the research team leader. The full text was obtained and thoroughly reviewed to determine if it met the inclusion criteria and objectives of the review. Articles were rejected if they did not answer the research questions.

Data extraction and synthesis
The included studies were then downloaded and retrieved by the researchers (N.M., A.M.). Data from the completed studies, including authors' names, article title, year, country, study location, study population, sample size, study objectives and summary of results, were extracted by the authors and collected in an Excel file. The results were summarised in a narrative synthesis. Prior to data extraction and analysis, the authors assessed the methodological quality of the included studies using the Newcastle-Ottawa Quality Assessment.

Assessment of methodological bias
The authors utilized Newcastle-Ottawa Quality Assessment Form for Cohort Studies (NOS) [25] to assess the risk of bias and ensure the study's quality. The NOS came from an ongoing collaboration between the Universities of Newcastle, Australia and Ottawa, Canada. According to Ma et al. [26], among the many tools, NOS is the most commonly used, which can also be adapted to specific topics. This tool has three parts: selection (4 questions), comparability (1 question) and outcome (3 questions). The final scores will be divided into three categories: good (3 or 4 stars in the selection domain and 1 or 2 stars in the comparability domain and 2 or 3 stars in the outcome/exposure domain), fair (2 stars in the selection domain and 1 or 2 stars in comparability domain and 2 or 3 stars in outcome/exposure domain) and poor (0 or 1 star in selection domain or 0 stars in comparability domain or 0 or 1 stars in outcome/exposure domain). All included studies received one star for the questions in each section of the checklists. Articles were selected if both reviewers agreed on the quality of the articles. In case of disagreement, the assigned reviewers consulted a third independent reviewer. The quality scores are shown in Table 1.

Result
The search was then carried out according to the PRISMA flow, as shown in Fig. 1. The initial search returned 1792 studies. 515 duplicate articles were removed and then the titles and abstracts of the remaining 1277 articles were reviewed to see if they answered the research questions. Of the 1277 articles, 18 were accepted and 1259 were excluded (313 were not focused on CRC, 930 were not related to green spaces, two were not in English, 14 were not primary. Thirteen articles were rejected because they did not answer the research questions, leaving a total of five articles.
Due to the considerable heterogeneity, the data are presented descriptively.

Characteristics of the included studies
This review covers five publications published between 2017 and 2022. All five articles were cohort studies, each from the United States [31], the United Kingdom [27], Germany [30], France [28] and Belgium [29], with high quality evaluated based on Newcastle-Ottawa Quality Assessment Form for Cohort Studies. The study population was aged between 30 and 69 years and the sample size ranged from 19408 to 2441566 participants. Recruitment took place from 1989 to 2010. The shortest follow-up period was five years and the longest was 27 years. Table 2 presents the characteristics of the included studies. Table 3 presents the description and interpretation of the GSs. The decision to include attributes was based on the broad definition found in the articles by Taylor and Hochuli [17] and Markevych et al. [32].

GS attributes
The attributes included in this review GS are the percentage of gardens and natural environment grouped as ecosystem [27], the recreational facilities and parks count [31], residential proximity to the various greenspaces, residential surrounding greenness [28], surrounding greenness using the Normalized Difference Vegetation Index (NDVI) [28][29][30] and surrounding green areas [29]. A further description of the attributes can be found in Table 3. Basically, all studies used the residential address as the reference point for measurement. To measure exposure, each study used different buffer sizes depending on the attributes. For example, the most common buffer size was 300 m used for the garden, and the natural percentage [27][28][29]. Sakhvidi et al. [28] have different buffers as they investigated different types of green areas: agricultural land, urban green areas and forests. One study [28] includes the data of the time window of exposure. A time-dependent approach was used by two studies [28,31] when looking for recreational facilites and parks. Four studies mentioned the specific time for measuring GS and CRC [27][28][29][30][31]. Three studies analysed the data of movers compared to non-movers and look for differences in the GS exposure.

CRC outcome
The CRC outcomes were categorized as the CRC incidence and mortality rate. Four studies reported GS exposure and CRC incidence [27,28,30,31], while one reported CRC mortality [29]. Only research from Canchola et al. [31] separated colon and rectal cancer while others studied on overall colorectal cancer. The findings are summarised in Table 4. Table 5 summarised the association between GS attributes with CRC. Only one study reported that a better ecosystem which includes the garden and natural environment, is associated with a lower risk of CRC [27]. Another study with a 27-year follow-up cohort suggested that greenspace has a protective role for colorectal cancers, but the findings were not statistically significant [28]. Similarly, Datzmann et al. [30] discovered no link between GS (NDVI) and CRC. Another study by Canchola et al. [31] found no significant associations between recreational facilities, park count, and colorectal cancer risk.

GS and CRC mortality
In their 13-year follow-up cohort study, Rodriguez-Loureiro did not find a significant connection between CRC mortality and GS  (greenness and green areas) [29].

Discussion
This review investigated the association between GS and CRC. According to the literature, the term "GS" appears in many academic articles, including architecture, urban planning, building science, biology, medicine, and health [8]. The term "GS" also refers to parks, gardens, yards, urban forests, and urban farms are examples of urban vegetation. Landscape vegetation includes forests and wilderness areas, street trees and parks, gardens and backyards, geological formations, farmland, coastal areas, and food crops [8]. The GS is measured in various ways, such as using normalized difference vegetation index (NDVI), street view, tree density, greenspace percentage, and landscape percentage from remote sensing methods. WHO [33] suggested that the percentage of green space on land cover and land use maps, such as the European Urban Atlas, could be an important indicator.
Secondary indicators include satellite-based NDVI and perception-based measures of urban GS. Some studies have used green space density indicators in conjunction with national or local land use/land cover datasets. Other studies have used international data, such as Coordination of Information on the Environment (CORINE) land cover data. Each map has a minimum unit. The mean NDVI value for an area is calculated using high-resolution imagery and serves as an indicator of the "greenness" of the environment. At a certain distance from the focal point of a geographic region, the area can be considered a "buffer" zone". These databases can be examined with different buffer sizes (100, 300, 500, 1000 and 3000 m) [34].
Because there is no universally accepted definition of "GS," even standardisation is favourable; however, forcing "GS" to mean the same thing everywhere is detrimental; thus, the GS accepted for inclusion in this review are the ecosystem (because it includes a garden and natural environment), recreational facilities and parks within the residence, and residential proximity to various types of GS surrounding green area and surrounding greenness. As a result, this review provides a relevant definition of the term for each study.
For now, no evidence supports the association between GS and CRC. A study by Rodriguez-Loureiro in their 13 years follow-up cohort study reveals that residing in GS (greenness and green areas) could minimize the risk of mortality from lung and breast cancer but not CRC [29]. The study also stated that the lack of association could be attributed to a lack of statistical power due to the smaller sample size and shorter follow-up period. Another study with a 27-year follow-up cohort suggested that greenspace has a protective role for colorectal cancers, but the findings were not statistically significant [28]. Their study had some limitations, including the fact that it focused on a different type of greenspace, that exposure ratings varied greatly, and that the study lacked statistical power. Similarly, Datzmann et al. [30] revealed no link between GS (NDVI) and CRC while Canchola et al. [31] found no significant associations between recreational facilities, park count, and colorectal cancer risk.
A better ecosystem also means healthy and balanced ecosystem, which include the green and natural environment might provide a greener and less polluted environment. Only one study in this review found that a better ecosystem, including the garden and natural environment, was associated with a lower risk of CRC [27]. There has been little research comparing the ecosystem and CRC to other cancers. Natural and artificial GS are considered ecosystem services as they fulfill basic needs such as food, water, and air, as well as regulating air quality, vector-borne disease, climate change, and facilitating living, recreational, and spiritual interactions with nature to enhance human well-being [35,36]. Increased exposure to better ecosystem strengthens the immune system by altering the human microbiome, provides long-term health benefits, lowers the incidence of non-communicable diseases and reduces mortality [37].
GS research in CRC is still restricted compared to other cancer such as lung, breast, and prostate. A meta-analysis found no statistically significant links between greenspace and breast, lung, or prostate cancer incidence [23]. A population-based case-control study in Madrid shows an association between urban GS and the reduction of childhood leukaemia incidence [38]. In a study conducted in Spain urban GSs, including gardens, zoos, and urban parks, lowered breast cancer risk [39]. GS was associated with a lower incidence of lethal prostate cancer in a study conducted in the United States [21] but contrary results showed that GS exposure increases prostate cancer mortality [29].
Agricultural land provides greenery, urban attractiveness, and food production, but also an increased risk of cancer. In a study by Sakhvidi et al. [28] observed an increased risk of prostate, breast, colorectal (but not significant), bladder, lung, and malignant melanoma of the skin in proximity to agricultural lands. The results also show that proximity to agricultural areas increases the risk of breast cancer in Spain [39]. Agricultural land can also be classified as GS, but the benefits do not resemble those of parks [40]. It has been proposed that increased pesticide exposure is linked to cancer [41]. The evidence for the other cancers was inconclusive; therefore, further studies will have to consider the other types of greenspaces (for example agricultural area) and evaluate type of cancer [23].
Canchola et al. [31] found no significant associations between recreational facilities, number of parks and risk CRC. The number, availability and accessibility of parks and recreation facilities can influence on physical activity in adults [42] and children [43]. However, the Dutch National Health Survey, found that distance to the nearest GS is inconsistently associated with physical activity and obesity [34] which support for that not necessarily mean that person who live closest to a park are more likely to visit a park, exercise and have lower body weight compared to who live further away. This supports that according to one study, a long distance between children's homes and the nearest park was associated with a significantly lower risk of obesity in urban children [44].
Surrounding greenness may promotes positive behaviour like physical activity, social interaction and stress relief [45]. The normalized difference vegetation index (NDVI) is used as a indicator of surrounding greenness in this review. Included studies emphasised that CRC outcome was not affected by GS exposures because the influenced by individual and organizational components. GS may have lower road density and hence reduced traffic, resulting in lower levels of traffic-related air pollutants, whereas trees may restrict the dispersal of traffic air pollutants and thus increase the concentration of air pollution in the roads [32]. Apart of the availability of green areas, behaviour is also a main factor. The surrounding greenness may have no or little effect on people's levels of physical activity. Social Cognitive Theory states that people are driven by both internal and external forces [46]. This concept proposes that behaviour and environmental factors affect human action (physical activity). The socioecological framework (SEF) strengthens the theory that the component of the behavioural and organizational impacts on cancer prevention and control. This paradigm has been utilized to strengthen cancer prevention and control initiatives including in the Pacific Region [47].
Spatial analysis methods used to investigate the relationships between distance to green space and health data [48]. The general approach for calculating the GIS distance is the Euclidean distance and the network distance. The Euclidean distance in Sakhvidi et al. [28] is used to measure distance of each residential address (as a point) to the nearest, different type of GS. A straight-line distance or Euclidean distance is the length of a straight line connecting two target points. However, there are other factors that can alter the calculation of the straight-line distance, such as obstacles and surface distances. Nowadays, distance measurement has evolved from Euclidean distance to network-based distance [48]. The network distance is determined using network analysis techniques that calculate the shortest distance or travel time between two points in the network [49]. It is assumed that using network has better approximation to the real world. In this approach, the distance between two points is measured by the shortest path using network analysis. Compared to Euclidean distance, network distance is more accurate in estimating accessibility because residents use roads. However, to obtain more accurate data, network distance requires the creation of more detailed geospatial data in the software GIS. Using an inappropriate method to examine distance and access to green space can directly influence the direction (and extent) of the association and therefore limit its relevance in broader geographical contexts [48].
The research into GS was motivated by the positive health outcomes by acting as biological, chemical, physiological, psychological, and environmental agents to improve health and reduce disease risks [50]. Studies have linked greenspace and cardiovascular disease (CVD) outcomes, such as lower CV mortality, inspiring researchers to look for similar results in CRC [51]. GS can help to improvise the inflammatory profile through many interventions such as forest bathing inspired by traditional Japanese nature immersion to reduces stress and inflammation [52]. There is also the different profile of stress, antioxidant and cytokine between urban and forest environment exposure that can be used to connect it with CRC [53]. GS strategies such as urban planning involving GS could consider working with an interdisciplinary team of environmental specialists, public health professionals, epidemiologists, anthropologists and psychologists [54]. Local stakeholders and community organizations can participate in GS initiatives by identifying appropriate locations and initiatives. Creating new or modifying GS must be tailored to the needs of the public, particularly in disadvantaged communities. City planners play an important role in preventing the development of GSs. The best agricultural land and natural assets like parks, lakes, and riverfronts must be protected especially in highly populated places. Integrated city development incorporates ecological, environmental, and social justice considerations into land investment and development decisions [55]. Urban planning initiatives that protect GS align with promoting "sustainable cities" [56].

Challenges related CRC and GS research
Greenspace is directly and indirectly connected to other risk variables such as sun exposure, physical activities, obesity, and air quality, making it challenging to be evaluated [57]. The CRC investigations also need to consider the site of cancer, the type of greenspace, the measure of exposure, and the study's geographical location. The varying GS measurements utilized in that research may have led to conflicting findings [44]. The exposure to GS reduced risk of CRC in at least three ways, by decreases air pollutant Chen et al. [27] Incidence UK Biobank (UKB) and coded using ICD-9 or ICD-10. Overall, separate analyses on colon and rectal cancer 2) Mortality data from California death certificate files and the National Death Index.
The first diagnosis of invasive CRC (ICD for Oncology-3 Sakhvidi et al. [   concentrations [58], encouragement for walking and physical activities [59] and potential reduction in stress (the risk of rectal cancer but not colon cancer) [60]. However, the studies only examined exposure GS and not actual benefits such as reduction in pollutant concentration, increase in physical activity or stress reduction. None of the included studies examined the temporal relationship between exposure GS and outcome CRC (incidence and mortality), so the exact mechanism leading to diagnosis/death CRC or the possibility that CRC occurred several years/decades before diagnosis could not be investigated in this area. Lack of accuracy in reporting information may occur due to self-reporting [39]. The lack of association could be explained the other factors such as social background, safety, weather, mental health, and stress [39]. Socioeconomic background can have an impact on GS. Individuals with higher incomes and education levels have a greater opportunity to benefit from GS for their health than those in lower-income groups [61]. Exposure to varying levels of GS, duration, health status, and stress levels can all result in different outcomes. The study population may impact the results, so further research and sub-analysis may reveal some associations.
It is difficult to truly quantify the impact of GS because there are no specific indicators, as opposed to diet, where food directly affects human biological function. The pathway involved in the CRC mechanism is difficult to determine without using specific biomarkers and measuring the level of exposure to greenness. The mechanism of CRC carcinogenesis caused by GS is indirect and unclear. GS may have little influence on carcinogenesis through exposure to pollution [30], stress [22], physical activities [21] and obesity [62]. Molecular carcinogenesis research has advanced significantly, and scientists have uncovered numerous carcinogenic events. The interaction of genes and their environments revealed that genetic or epigenetic modifications displayed later in life may be influenced by what is exposed today.

Limitation and strength
Despite the higher quality of the available cohort studies on the association between GS and cancer, all studies found heterogeneous results for different subgroups. The main limitations that make it difficult to compare the results are that the association we observed is heterogeneous within and between studies, which is due to the studies having different exposure ratings, confounders and the power of the study in which the studies were involved. We found only five cohort studies on the association between green space and CRC, possibly due to the fact that the study relied on three databases, which might limit the number of relevant studies. Accepting articles written in English only could limit the number of potential native language studies to avoid additional costs, time and interpretation errors.
Many cohort studies contributed to identifying various GS-related risk factors associated with CRC incidence or mortality at the population level. Further randomized controlled trials that involve a large population may be required to validate our findings. With the availability of advanced technologies and data analysis, GS research has become an appealing method of discovering and monitoring environmental links with cancer trends.

Conclusions
This review addressed the current state of knowledge regarding the relationship between GS and CRC. According to the findings, there is currently no link between CRC and GS. GS is critical in promoting physical activity. Proximity to GS provides health benefits and reduces the risk of certain diseases, allowing those with access to choose the best disease prevention practice. As a result, comprehensive city planning is required to create a future environment that reduces CRC incidence and mortality. Validation of these findings in other studies and settings to further explore and advance our understanding of the potential health benefits of GSs.

Author contribution statement
Noor Azreen Masdor, Azmawati Mohammed Nawi, Rozita Hod: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper. Maryam Fatimah Abu bakar: Analyzed and interpreted the data; Wrote the paper.

Data availability statement
No data was used for the research described in the article.